2-chloromethyl-4-cycloalkyl-quinazoline-3-oxides



United States Patent 3,503,974 2-CHLOROMETHYL-4-CYCLOALKYL-QUINAZOLINE-3-OXIDES Leo Berger, Montclair, and Leo Henryk Sternbach,

Upper Montclair, N.J., assignors to Hoffman-La Roche Inc., Nutley, N.J.,a corporation of New Jersey N0 Drawing. Application Apr. 5, 1967, Ser.No. 628,528,

now Patent No. 3,389,176, which is a division of application Ser. No.137,047, Sept. 11, 1961, now Patent No. 3,338,886. Divided and thisapplication Feb. 8, 1968, Ser. No. 703,909

Int. Cl. C07d 51/48 US. Cl. 260-251 2 Claims ABSTRACT OF THE DISCLOSUREThis invention relates to novel 2-chloromethyl-4-cycloalkylquinazoline-3-oxides which are chemical intermediates in the preparationof novel benzodiazepin compounds selected from the grouping consistingof 5-cycloalkyl-3H-l,4-benzodiazepin-2 1H) -ones, pharmaceutical- 1yacceptable acid-addition salts thereof, 2-loweralkylamino-5-cycloalkyl-3H-1,4-benzodiazepines 4-oxides andpharmaceutically acceptable acid-addition salts thereof. Preferred arethose benzodiazepine compounds of the above group wherein the 7-positionis either unsubstituted or substituted by a halogen or nitro group. Thenovel benzodiazepine compounds are useful as tranquilizers, andanticonvulsant agents.

CROSS REFERENCES TO RELATED APPLICATIONS This application is adivisional application of Ser. No. 628,528, filed Apr. 5, 1967, now US.Patent No. 3,389,- 176, issued June 18, 1968, which is a divisionalapplication of Ser. No. 137,047, filed Sept. 11, 1961, now US. PatentNo. 3,338,886, which is a continuation-in-part of Ser. No. 131,750,filed Aug. 16, 1961, now US. Patent No. 3,268,586, issued Aug. 23, 1966and application Ser. No. 51,262, filed Aug. 23, 1960, now abandoned.

This application is also related to application Ser. No. 324,850, filedNov. 19, 1963, and application Ser. No. 324,879, filed Nov. 19, 1963,now US. Patent No. 3,179,- 656, which are both divisional applicationsof the above application Ser. No. 131,750, filed Aug. 16, 1961.

DETAILED DESCRIPTION OF THE INVENTION The novel benzodiazepine compoundsof the invention are useful as pharmaceuticals, more particularly astranquilizers, by virtue of their depressant action upon the centralnervous system. They also are useful as anticonvulsant agents. Thepharmacological activity of the compounds is demonstrated in theinclined screen test, the foot shock test, the anti-maximal electroshocktest, and the anti-pentamethylenetetrazol test. The compounds can beadministered internally, for example, orally or parenterally and can becompounded into dilferent conventional pharmacutical forms such astablets, capsules, lozenges, suspensions, suppositories, solutions andthe like. Dosage can be adjusted to individual requirements.

3,503,974 Patented Mar. 31, 1970 cycloalkyl and acid-addition saltsthereof; wherein R is selected from the groups consisting of hydrogenand lower alkyl and R is selected from the group consisting of hydrogen,halogen and nitro.

As used in the disclosure the term lower alkyl refers to both straightand branched chain carbon-hydrogen radicals such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and the like. The term halogenincludes all four halogens viz. iodine, bromine, chlorine and fluorine.The term cycloalkyl includes cycloaliphatic radicals, for example,cyclo-lower alkyl groups such as cyclopentyl, cyclohexyl, cycloheptyland the like. Especially preferred are those compounds wherein thecycloalkyl group is cyclohexyl.

The novel benzodiazepines of Formula I above can be prepared by avariety of routes. Used as starting materials are 2-aminophenylcycloalkyl ketones of the formula wherein R is selected from the groupconsisting of hydrogen, halogen and nitro. The ketones of Formula IIabove are themselves novel compounds and form a part of the presentinvention.

Compounds of Formula I above can be prepared by reacting a ketone ofFormula II above with hydroxylamine to form a corresponding ketoxime ofthe formula cyeloalkyl wherein R is selected from the groups consistingof hydrogen, halogen and nitro haloacetylating said ketoxime,dehydrating the resultant haloacetylated ketoxime to a quinazoline ofthe formula (IV) cycloalkyl wherein R is selected from the groupconsisting of hydrogen, halogen and nitro and reacting said quinazolineof Formula IV above with ammonia or a lower alkyl primary amine toobtain the corresponding compound of Formula I above.

EXAMPLE 1 Cyclohexyl' magnesium bromide was prepared under Grignardconditions from 2.7 g. of magnesium turnings and 20.2 g. of cyclohexylbromide in 50 cc. of anhydrous ether in the usual manner. Afterrefluxing the Grignard solution for 3 hours to complete the formation ofcyclohexyl magnesium bromide, it was added slowly under anhydrousconditions to a solution of 17.3 g. of 2-methyl-6- chloro 4H 3,1benzoxazin-4-one in 200 cc. of dry benzene containing 50 cc. of dryether under cooling (-5 C.) with constant stirring.

Upon completion of the addition, the stirring was continued while thetemperature rose to room temperature. After several hours at roomtemperature, the Grignard complex was decomposed with 30 cc. of 6 N HClmixed with ice.

The acidified solution was then concentrated to dryness and the residuemixed with a solution of 26 cc. concentrated H01 in 160 cc. ethylalcohol. The solution was refluxed for 2 hours, concentrated to dryness,the residue dispersed in water, and made alkaline with solid potassiumcarbonate. The insoluble oil was extracted with benzene and the benzenesolution separated, dried over anhydrous sodium sulfate, filtered andconcentrated to dryness. The amorphous residue was boiled out withpentane to exhaustion and the pentane solution was concentrated todryness and the crystalline residue was recrystallized from pentane.There was obtained 2.8 g. of bright yellow needles melting at 115 1162-amino-5- chlorophenyl cyclohexyl ketone.

Analysis.-Calcd. for C H NOCl (MW 237.5) (percent): C, 65.70; H, 6.74.Found (percent): C, 65.63; H, 6.71.

EXAMPLE 2 A solution of cyclohexyl magnesium bromide, prepared from 3.0g. of magnesium and 22.4 g. of cyclohexyl bromide by the methoddescribed in Org, Syn. Coll. vol. I, 186, 1941, in 60 ml. of ether wasadded slowly to a stirring solution of 16.1 g. of 2 methyl 4H 3,1-benzoxazin-4-one in 300 ml. of ether. The addition took approximately 1hour. During the addition, the temperature was maintained by means of anice bath between 0 to 2. After the addition was complete, the stirredreaction mixture was allowed to come to room temperature (22). Thereaction mixture was again cooled by means of an ice bath and 20 ml. ofethanol added with stirring, followed by 100 ml. of water and finallythe reaction mixture was made acid with dilute hydrochloric acid. Theether was removed on a steam bath and 200 ml. of ethanol and 30 ml, ofconcentrated hydrochloric acid were then added. After the reactionmixture had remained on a steam bath'for 4 hours, it was cooled byadding ice, and the pH was adjusted to 5 with solid potassium carbonate.The product that separated was extracted with chloroform and the extractdried over sodium sulfate. After the desiccant had been filtered off,the filtrate was concentrated on a water bath. The residue was distilledat reduced pressure; B.P. 125-130 at 0.12 mm. The distillate wascrystallized from petroleum solvent and yielded yellow needles of2-aminophenyl cyclohexyl ketone melting at 7475 (uncorr.).

EXAMPLE 3 1 g. of 7 nitro-5-cyclohexyl-3H-1,4-benzodiazepin-2- (1H)-onewas dissolved in a solution of 10 ml. of ethanol and 10 ml. of 3 Nhydrochloric acid. 3 ml, of concentrated hydrochloric acid was added.The solution was refluxed for 7 hours. 20 ml. of water was then added tothe Warm reaction mixture. After the mixture had cooled to roomtemperature, it was allowed to remain overnight in the ice box. Themixture Was filtered and the precipitate was dried yielding Z-amino 5nitrophenylcyclohexyl ketone melting at l24125 (uncorr.).

Analysis.Calcd. for C H N O (percent): C, 62.9; H, 6.45; N, 11.30. Found(percent): C, 62.75; H, 6.07; N, 10.81.

EXAMPLE 4 Cyclopentylmagnesium bromide was prepared from 2.7 g. ofmagnesium turnings and 20.2 g. of cyclopentyl bromide in 50 cc. ofanhydrous ether under Grignard conditions. After refluxing the Grignardsolution for 3 hours to complete the formation of cyclopentylmagnesiumbromide, it was added slowly under anhydrous condition to a solution of17.3 g. of 2-methyl-6-chloro-4H-3,l-benzoxazin-4-one in 250 cc. of drybenzene at room temperature under constant stirring. The internaltemperature rose to 42. Upon completion of the addition, the reactionmixture was refluxed for 1 /2 hours, cooled to room temperature anddecomposed with 30 cc. of 6 N hydrochloric acid mixed with ice shavings.The acidified mixture was filtered through a sintered glass funnel andthe solution concentrated to dryness. The residue was dissolved in 160cc. of ethanol and 26 cc. of concentrated hydrochloric acid added. Thesolution was then refluxed for 2 hours, concentrated to dryness and theresidue suspended in water. The product was made basic with potassiumcarbonate in excess, and the insoluble oil that separated was extractedwith benzene. The benzene solution was separated, washed with water,dried over anhydrous sodium sulfate, filtered and concentrated todryness. The residue, a yellow oil, was purified by distillation underreduced pressure yielding 2-amino-5- chlorophenyl cyclopentyl ketoneboiling at 132136 at 15 mm.

Analysis.Calcd. for C H NOCl (223.5) (percent): C, 64.4; H, 6.26; N,6.26. Found (percent): C, 64.64; H, 6.30; N, 6.08, 6.03.

EXAMPLE 5 A solution of 16.8 g. of2-methyl-6-chloro-4H-3,l-benzoxazin-4-one in 250 cc. of benzene wasprepared with slight warming in a 3-neck round bottom flank. Thesolution was then cooled to room temperature. In another 3-neck roundbottom flaskunder Grignard conditionscycloheptylmagnesium bromide wasprepared from 2.7 g. magnesium turnings, 24.0 g. of cycloheptyl bromidein 70 cc. of ether. After 4 hours of refluxing, the formation of theGrignard complex was complete. The cycloheptylmagnesium bromide solutionwas added slowly to the benzoxazinone solution at room temperature withconstant stirring. The reaction mixture was then heated to refluxtemperature, refluxed for 1 hour, cooled to room temperature anddecomposed with 30 cc. 6 N hydrochloric acid and ice.

An insoluble white precipitate was filtered off and the mother liquorwas concentrated to dryness. The residue was dissolved in 160 cc. ofethanol, 26 cc. of concentrated hydrochloric acid added, and theresultant solution refluxed for 5 hours. The solution was thenconcentrated to dryness, water added, and the suspension made basic withsolid potassium carbonate. The oil that separated was dissolved inbenzene, washed several times with water, and the benzene solution driedover anhydrous sodium sulfate. The drying agent was removed byfiltration and the benzene solution was concentrated to dryness to leavea thin syrup. This was distilled in vacuum to yield a liquid productboiling at 132-140/0.08 mm. Upon treatment with pentane yellowcrystalline 2-amino-5-chlorophenyl cycloheptyl ketone was obtainedmelting at -82.

EXAMPLE 6 A mixture of 1 g. of Z-amino-S-chlorophenyl cyclohexyl ketone,1 g. of hydroxylamine hydrochloride, 5 ml. of ethanol, and 5 ml. ofpyridine was refluxed on a steam bath for 2.5 hours. After the volatilecomponents had been removed under vacuum on a water bath, the residuewas triturated with 20 ml. of water and filtered. The filter cake waswashed with water and then dried for several hours yielding2-amino-5-chlorophenyl cyclohexyl ketoxime melting at 192-194 (uncorr.).This oxime is a mixture of the syn. and anti isomers.

EXAMPLE 7 A mixture of l g. of syn. and anti2-amino-5-chlorophenylcyclohexyl ketoxime and ml. of glacial acetic acidwas heated with occasional swirling on a steam bath. When thetemperature reached 50, 0.6 ml. of chloroacetylchloride was addedrapidly. The reaction was mixed thoroughly and allowed to remain at roomtemperature overnight. After the volatile components had been removedunder reduced pressure on a water bath, the residue was dissolved in 20ml. of acetone, allowed to stand at room temperature for several hours,and filtered. The filtrate was concentrated under vacuum and the residuewas partitioned between 500 ml. of ether and 200 ml. of water. After theaqueous portion had been discarded, the ether layer was washed withdilute potassium carbonate and then water. The ether solution was thendried with sodium sulfate. After the desiccant had been removed byfiltration, the filtrate was concentrated and the residue wascrystallized from a small amount of acetone yielding6-chloro-2-chloromethyl 4 cyclohexylquinazoline 3- oxide melting at125-127 (uncorr.).

EXAMPLE 8 600 mg. of 6-chloro-2-chloromethyl 4 cyclohexylquinazoline3-oxide was added with stirring to 30 ml.

of cold (+3) 25% monomethylamine in methanol. The solution was stirred0.5 hour at ice bath temperature and allowed to come to room temperatureslowly, with stirring. A trace of crystals that appeared after thereaction was kept overnight in the refrigerator was removed byfiltration, and the filtrate was concentrated to dryness at reducedpressure. The residue was partitioned between 200 ml. of ether and 100ml. of water. The ether layer was separated and washed three times withml. of water. Filtration was used to remove the desiccant after theether solution had dried over sodium sulfate and the filtrate wasconcentrated under reduced pressure. The residue was crystallized twicefrom methanol yielding 7- chloro-2-methylamino-5-cyc1ohexyl 3H1,4-benzodiazepine 4-oxide melting at 230-231" (uncorr.).

We claim:

1. A compound of the formula cycloalkyl wherein R is selected from thegroup consisting of hydrogen, halogen and nitro, and said cycloalkylgroup contains from 5 to 7 carbon atoms.

2. The compound of claim 1 which is 6-chloro-2-chloromethy1-4-cyclohexylquinazoline-3-oxide.

References Cited UNITED STATES PATENTS 3,389,176 6/1968 Berger et al260-566 ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner

